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Synthetic enkephalins. Addicting properties and conformational studies in solution
International Journal of Peptide and Protein Research
|July 1, 1979
Summary
The addicting properties of [Leu5]-enkephalin are conserved in the LSer3 analogue but lost in L-Ser2 and L-Cha4 derivatives. Conformation in solution does not clearly correlate with biological activity, suggesting a beta-turn receptor-bound structure.
Area of Science:
- Neuroscience
- Biochemistry
- Molecular Biology
Background:
- Opioid peptides like [Leu5]-enkephalin play crucial roles in pain modulation and reward pathways.
- Understanding the structure-activity relationships of enkephalin analogues is vital for developing novel analgesics and addiction therapies.
Purpose of the Study:
- To investigate the impact of specific amino acid substitutions on the addicting properties and solution conformation of [Leu5]-enkephalin.
- To explore the correlation between peptide conformation and biological activity.
Main Methods:
- Synthesis of [Leu5]-enkephalin analogues with modifications at key positions (LSer3, L-Ser2, L-Cha4).
- Fluorescence spectroscopy to detect hydrogen-bonded tyrosyl hydroxyl groups.
- Near-ultraviolet circular dichroism to assess conformational changes.
- Assessment of addicting properties in mouse models.
Main Results:
- Addicting properties were conserved in the LSer3 analogue but lost in L-Ser2 and L-Cha4 derivatives.
- Fluorescence measurements indicated hydrogen-bonded tyrosyl OH groups in [Leu5]-enkephalin and its LSer2 analogue.
- Phe4/Cha replacements altered near-UV dichroism but not hydrogen-bonding equilibria.
- A specific positive dichroism was observed for [Leu5]-enkephalin and its cyclohexylalanyl derivative in solution.
Conclusions:
- No direct correlation was found between observed solution conformations and biological activity.
- A Type II beta-turn conformation, with residues 2 and 3 at the corners, is proposed for enkephalin bound to the receptors involved in the bioassay.